This program will prepare Amy M. Pastva, PT, PhD, CCS, for a career as an independent clinician-scientist in academic research medicine, specializing in the study of allergic lung disease. Dr. Pastva has been pursuing rigorous training in cell biology and immunology at Duke University to address an important public health issue, asthma pathogenesis. Jo Rae Wright, PhD, an authority in lung surfactant biology, and Monica Kraft, MD, an expert in asthma pathogenesis, will serve as her mentors. The proposal focuses on the role of lung surfactant protein (SP)-A as a regulator of immune host defense in asthma. Although acute infectious disease models show that SP-A inhibits inflammation and enhances pathogen clearance, relatively little is known about its role in allergic asthma. Using the ovalbumin (OVA) model of allergic asthma, preliminary data show that SP-A null (SP-A-/-) mice have attenuated airway hyperresponsiveness (AHR) despite increased T Helper (Th) 2-associated inflammatory indices and increased effector memory CD4+ T cells in their lungs compared to WT mice. Treatment with a general inhibitor of nitric oxide synthases (NOS), the enzymes that catalyze nitric oxide (NO), completely abrogated the attenuated AHR. Thus, the hypothesis of this proposal is that SP-A deficiency in allergic asthma results in enhanced nitric oxide (NO) bioavavailability, which reduces AHR, and results in enhanced CD4+ T cell activation, which promotes Th2-associated inflammation. Aim 1 will determine the mechanisms by which SP-A regulation of NO species modulates AHR in allergic lung disease. The expression levels and activity of NO species will be examined with and without NOS inhibition in sham and OVA treated WT and SP-A-/- mice. Aim 2 will determine the role of SP-A in mediating NO independent and dependent regulation of T cell phenotype and function. CD4+ T cell subsets will be phenotypically and functionally characterized in ex vivo assays, syngeneic co-culture assays, and adoptive transfer studies. Aim 3 will explore the efficacy of using SP-A replacement in allergic lung disease. Together with reports showing reductions in the levels of SP-A in asthma, data suggest that SP-A deficiency activates an immune response to an allergenic insult whilst maintaining airway patency. Uncovering the mechanisms by which this unique paradigm exists may lead to new insights in lung immunobiology and to the development of novel therapies that may influence the morbidity and mortality of asthma.